Research Area: Challenge Area: Bioethics Challenge Topic: 02-OD (OSP)-105* More than two million Americans with cancer, heart disease, infectious diseases, diabetes, neurological disorders and other conditions are enrolled in clinical research in the United States each year. For many of these patient-subjects, participation is viewed, by them and by their physicians, as a means of treating or responding to their medical condition. Moreover, the infusion of billions of dollars into comparative effectiveness research and quality improvement research over the coming years ensures that soon many more patients will be receiving care that, in one way or another, is integrated with clinical and health services systems research. Indeed, there is growing recognition that high value health care will be achievable only if the outcomes of medical interventions and practices are continuously under study. As such, research methods and funding are rapidly changing to respond to this practical need. . The challenge with this shifting environment is to adapt traditional paradigms for the ethics of research to this new paradigm for a research and treatment interface, where research and treatment are increasingly, yet to varying degrees, integrated in what some have called the total learning environment. This project is intended to begin to fill the knowledge and policy gap in research ethics created by the increasing integration of research with treatment. Useful policy guidance is critically needed that is responsive to the integrated nature of research and treatment across research approaches, including the three research areas on which this project will focus: " Traditional clinical trials of unapproved drugs/devices;" Comparative Effectiveness research;" Quality Improvement research. Without such guidance, much needed research may be inappropriately impeded by oversight norms ill suited to this evolving context. Thus, we expect this work to be a significant down payment on much needed rethinking of the how best to craft human research protections for the broadening federal research program and the health system of the future in which research and treatment are increasingly intertwined. This project will accomplish its work through ongoing, collaborative meetings of a core group of six experts in research ethics, clinical trials, comparative effectiveness, quality improvement, and/or public policy. Through sub-group and core group interactions, the development of rich case studies, and empirical data collection, this project will produce a conceptual analysis that considers a research-treatment interface rather than exclusively a separation, and will produce policy guidance and safeguards relevant to our evolving research agenda. The aims of this project include: Aim 1: Produce a clear, conceptual analysis that defines and characterizes the constitutive elements of "research" and "treatment" through the development of rich case studies of specific examples of (a) clinical trials of unapproved drugs and devices (CTUn);(b) comparative effectiveness (CE) research;and (c) quality improvement (QI) research, against which the conceptual analysis can be tested and refined;Aim 2: Examine the implications of this conceptual analysis for the moral and policy purposes to which the research-treatment distinction has been and continues to be put, with particular focus on rich case studies developed from CTUn, CE, and QI research;Aim 3: Conduct empirical research with investigators who conduct CTUn, CE, and QI research to (a) list a range of designs and examples within their area and discuss how constitutive elements of research and treatment apply;and (b) later, with additional inclusion of federal officials, to elicit reactions to draft conceptual and moral analyses and policy recommendations for feasibility and applicability;Aim 4: Based on our conceptual, moral, and empirical findings, develop policy guidance and safeguards for research participants in CTUn, CE, and QI research specific to investigators, to informed consent, and to research oversight. This project examines the research-treatment interface in the context of traditional clinical trials, comparative effectiveness research, and quality improvement research. Through the regular interaction of a small, collaborative expert working group, development of rich case studies, and empirical data collection, we will draft an original conceptual framework for the research-treatment interface as well as policy recommendations for research oversight and informed consent.